What Is the Outlook for Treatment De-Intensification Strategies for Head & Neck Cancer?

De-intensifying cancer treatment can make a profound difference for patients by reducing debilitating side effects. When it comes to making these treatment decisions in head and neck cancers, the stakes are incredibly high. Oncologists, surgeons and radiation oncologists must precisely balance the potential to reduce toxicities with the risk of undertreating patients.

“De-intensification can have tremendous benefit for patients with head and neck cancer because many of the side effects can have a large impact on their short- and long-term quality of life. However, if treatment de-intensification comes at the price of increased chances of disease relapse, that’s a major concern because salvage therapy isn’t as effective,” says Shlomo Koyfman, MD, a radiation oncologist with Cleveland Clinic Cancer Institute. “In these high-stakes situations, determining the risk/reward benefit can be daunting.”

Dr. Koyfman and his team are working to bring greater real-world evidence and clinical research to support these decisions.

Background

Historically, many patients with head and neck cancers required major surgery, followed by chemotherapy and radiation. They often faced intense short-term toxicities, such as mouth burns, taste loss, fatigue, pain, life-threatening infections or hearing loss. Many required feeding tubes. Long-term side effects from radiation involved severe dry mouth, swallowing dysfunction and damage to the jawbone. Radiation-induced malignancy has also been a growing concern, with more younger patients experiencing secondary cancer years or even decades after initial treatment.

Emerging treatment methods

Newer treatment techniques are aimed at reducing some of these risks.

Transoral robotic surgery makes it easier for surgeons to access hard-to-reach growths in the back of the throat. The instrumentation used in this procedure allows for greater precision and pathologic evaluation of the extent of disease. Frequently, successful surgery allows for dramatic reduction in the doses of radiation or chemotherapy required. “In some of these cases, particularly in young people, we’re able to forgo radiation and chemotherapy entirely,” says Dr. Koyfman.

Dose-reduced and response-adapted radiation is another approach to de-intensification. Cleveland Clinic physicians were among the first in the country to reduce the elective radiation dose from 56Gy to 30Gy, dramatically lowering the dose to critical normal tissues. In patients with bulkier, more advanced stages of oropharynx cancer, induction chemotherapy with or without immunotherapy can induce dramatic responses.

During the subsequent concurrent chemoradiation phase of treatment, radiation doses can often be safely reduced to areas that responded well to systemic therapy. The increasing use of induction systemic therapy lowers the burden of local therapy while minimizing the risk of distant metastases.

Reductions in radiation doses protects normal surrounding tissue such as the jawbone, swallowing muscles and vocal cords. It also lessens the burden on patients since they need fewer visits. “Lowering the intensity of radiation makes a huge difference in terms of patients’ quality of life,” explains Dr. Koyfman. “For example, we used to need to place feeding tubes in the majority of patients. Now it’s less than 10% of our patients who require them.”

Personalizing care

Cleveland Clinic believes in a personalized approach to care delivery.

In terms of IMRT planning, the team has developed protocols to achieve the optimum radiation dose distribution for each patient. Instead of following more generic oropharynx cancer-specific objectives, Cleveland Clinic physicians develop individual patient-specific objectives, customizing the constraints based on the characteristics and location of the tumor as well as surrounding lymph nodes. These constraints are used by radiation dosimetrists to optimize the patient’s plan far beyond the more standard generic dose constraints used in “scorecards” or national protocols. This allows for the radiation to be more finely targeted at the areas in need while avoiding healthy tissue.

Cleveland Clinic is among a handful of academic cancer centers leading the use of this individualized approach. Their outcomes have surpassed what national protocols recommend.

Precision oncology also plays a role in de-intensification efforts. In HPV-related disease, circulating HPV DNA is monitored throughout the treatment course and is often used as an adjunct to make therapeutic decisions. For non-HPV-related cancers, aggressive surgery, often with advanced free-flap reconstruction, remains a mainstay of therapy. Cleveland Clinic is helping to lead a national phase 3 study investigating whether it’s feasible to eliminate a year of adjuvant immunotherapy for certain patients whose circulating tumor DNA negativizes after surgery. 

Notable research

Recent studies have further informed de-intensification efforts.

• A phase 3 trial showed that the use of intensity-modulated proton therapy reduced the rate of feeding tube use compared to intensity-modulated photon therapy. Proton beam therapy is being increasingly utilized in head and neck cancers.
• The 30-ROC study led by Memorial Sloan Kettering Cancer Center demonstrated the potential to reduce radiation doses from 70 Gy to 30 Gy in patients with HPV-related oropharyngeal cancers who showed high tumor oxygenation. Those tumors that showed relative hypoxia before and during treatment were treated to the standard high dose of 70 Gy. The researchers found this approach was pursued in approximately 80% of patients and resulted in impressive control rates and much reduced toxicity. “Reductions of radiation in this level can mean a dramatic reduction in side effects,” says Dr. Koyfman. These research outcomes have led to a phase 3 study validating those results.
• The OPTIMA II trial published by the University of Chicago demonstrated that treating patients with HPV+ oropharyngeal cancer using neoadjuvant nivolumab and chemotherapy followed by response-adjusted locoregional therapy was safe and feasible. Cleveland Clinic is planning to participate in a follow-on study investigating the use of immunotherapy vs. combined immunotherapy/chemotherapy prior to chemoradiation for locally advanced head and neck cancer.

Dr. Koyfman cautions that not all de-intensification efforts have been successful. “There have been some national studies that did not work because they reduced the ability to cure patients. It’s incumbent on us to analyze our data and outcomes to make very careful decisions when it comes to de-intensification so as not to compromise cure. We also need to choose patients carefully.

“Our philosophy is to use everything at our disposal, including advanced imaging technologies, tumor genomics, circulating tumor DNA, biomarkers and response to initial therapy, and integrate all of these data points to make informed decisions in identifying candidates for de-intensification.”